Marijuana is the most commonly used illicit substance among adolescents in the United States. Marijuana has profound effects on cognition, memory, and psychomotor skills. Optimal performance in these domains is critical for adolescents to achieve the necessary milestones for transition to a productive adult life. In spite of this serious problem with potentially long-lasting consequences, there has been minimal investigation targeting the development of effective treatments, particularly medication treatments, for cannabis dependence in this vulnerable age group. A potential avenue for exploration is the development of medication, targeting neurobiological changes associated with cannabis dependence, to complement psychosocial interventions. Promising preclinical and preliminary clinical research indicates a potential role for N-Acetylcysteine (NAC), via glutamate modulation, in the treatment of substance use disorders. With the current climate of extraordinary caution surrounding the use of psychotropic agents in children, NAC has the advantage of over- the-counter availability and established pediatric safety record over decades of clinical use, making it a particularly appealing candidate for research in adolescents. Building upon encouraging pilot data, a placebo-controlled trial of NAC in cannabis dependent adolescents is proposed. Participants will be randomized to receive either NAC or matched placebo for eight weeks, with additional post-treatment follow-up at twelve weeks. All participants will concurrently participate in a contingency management (CM) intervention, designed to enhance study retention and complement medication effect targeting marijuana cessation. Urine cannabinoid tests will be performed twice weekly throughout the trial, and cognitive/impulsivity testing will occur before, during, and after treatment. The primary hypothesis is that participants receiving NAC + CM will exhibit significant reduction in marijuana use (as measured by number of negative urine cannabinoid tests) compared with participants receiving placebo + CM. A secondary hypothesis is that reduction in marijuana use (as measured by number of negative urine cannabinoid tests) will be associated with improvement in cognitive/impulsivity test performance. Another secondary hypothesis is that participants with co-morbid nicotine dependence receiving NAC + CM will exhibit significant reduction in cigarette smoking (as measured by urine cotinine verified self- report) compared with participants receiving placebo + CM. Results of the proposed study may contribute a novel step in treatment development for cannabis dependent adolescents. The identification of a well-tolerated, effective pharmacological treatment to complement existing psychosocial interventions would represent a significant advance and could yield tremendous public health impact. PUBLIC HEALTH RELEVANCE: Marijuana use in adolescence is a serious problem with potentially long-lasting consequences. To date, there has been minimal effort to develop medications to help treat adolescents who are addicted to marijuana. Thus, the proposed study will investigate N-Acetylcysteine (NAC), combined with an evidence-based treatment (Contingency Management), to help adolescents quit using marijuana.